NEURO_BBB

Question 1

What are some conditions where the BBB can break down?

Answer 1

Progressively: aging, disease, infection
Temporarily: post MI, following marked rise in BP, after injection of hypertonic solutions

Question 2

what is the purpose of adherens junctions in the BBB?

Answer 2

they stabilize the cell-cell interactions in the junctional zone

Question 3

what are some of the enzymes that give the BBB a dynamic metabolic activity?

Answer 3

MAO, gamma-glutamyl transpeptidase, alkaline phosphatase, peptidases, nucleotidases, cytochrome P450

Question 4

how can large molecules like abs, lipoproteins, proteins, and peptides be transferred to the central compartment?

Answer 4

receptor mediated transcytosis or non-specific adsorptive-mediated transcytosis (receptors for insulin LDL, transferrin and laeptin are all involved in transcytosis)

Question 5

what kind of chemical substances penetrate the BBB easily?

Answer 5

water, CO2, O2, lipid soluble free forms of steroid hormones

Question 6

what kind of permeability is increased when the BBB is disrupted?

Answer 6

there is increased para-cellular permeability

Question 7

explain why there is an increased para-cellular mediated permeability with BBB disruption?

Answer 7

due to tight junction disruption, greater trans-cellular permeability through the upregulated transcytosis, and drug and toxin accumulation due to decreased efflux by PGP
-there is also basement membrane disruption and decreased nutrient transport

Question 8

what family of proteins is inducible in many cancers where they serve to mediate resistance to substrate therapeutics?

Answer 8

ABC family proteins

Question 9

what is a major type of active pump that causes problems with anticancer and antidepressants?

Answer 9

P-gp

Question 10

what is the octanol/water partition coefficient?

Answer 10

an experimental way to measure lipophilicity, it compares drug equilibration in the octanol (lipid) phase vs. the water (aqueous) phase

• the more lipid soluble a drug is the easier it gets into the CNS
• this equates to more rapid onset of drug activity and higher more effective drug levels in brain

Question 11

besides lipophilicity what are the other parameters that could prevent drugs from getting across the BBB?

Answer 11

protein-bound drugs and ionized drugs (e.g. quaternary amine) can’t get into the CNS
(in general all proteins and polypeptides are prevented from accessing the CNS)

Question 12

what is a name of a prodrug that accesses the CNS and then becomes activated there?

Answer 12

L-dopa (can lead to more effective central effects and less significant peripheral activity, esp. when used in conjunction w/ inhibitors of peripheral metabolism)

Question 13

drugs with a high lipid solubility have a _________duration of clinical effect as compared to drugs that are less soluble?

Answer 13

short duration of action

Question 14

explain the time course of a drug like pentobarbital as it relates to BBB

Answer 14

IV injection, drug passes easily from blood to brain, moves passively down the concentration gradient

• as concentration falls, the gradient is reversed and now the lipophillic drug redistributes out of the brain into other organs
• pt wakes up 15 mins later bc drug has left BBB

Question 15

what are some P-GP inhibitors?

Answer 15

amiodarone
cyclosporin
nifedipine
quinidine
verapamil

Question 16

how can the BBB make treating brain tumors dificult?

Answer 16

can’t get effective drug levels achieved in tumor (doxorubicin, trastuzumab doesnt penetrate)

• BBB prevents effective diagnosis (can’t do gadolinium enhanced MRI)
• –can only detect larger tumors once the integrity of BBB breaks down around the tumor

Question 17

what are the important factors for the effective treatment of CNS infections?

Answer 17

choosing antimicrobials that cross into the CSF to exceed the min. inhibitory concentration for respective infective agent

• susceptibility of infective agent to the drug
• bacterial growth rate
• size of infection
• sequestration of the abscess

Question 18

is there a way to modulate P-gp activity?

Answer 18

NO

Question 19

what is a physicians most appropriate action when encountering a drug that is not working as well due to p-gp activity?

Answer 19

choose a non p-gp substrate drug to achieve effective antidepressant levels in the brain

Question 20

polymorphisms in what gene predict response to antidepressant treatment?

Answer 20

ABCB1 gene (P-gp)

Question 21

how can you overcome a CYP polymorphism that may be negatively effectively your drug treatment?

Answer 21

you can simply adjust the dose up to a certain point

Question 22

how might antidepressants have activity on p-gp?

Answer 22

antidepressants are substrates for p-gp, and might function as competitive inhibitors of other molecules that are also substrates, preventing them from accessing the CNS

Question 23

some endogenous and clinical corticosteroids are substrates for what?

Answer 23

p-gp